Pathogenesis of Ocular Infections

Ocular infection can occur via exogenous inoculation (eg, trauma, casual contact, fomites, vectors, aerosolization, sexual contact, contiguous adnexal disease, upper respiratory tract via the nasolacrimal duct), which is enhanced by conditions facilitating contact with the pathogen, or hematogenous seeding, which is rare. The initiation, severity, and characteristics of subsequent infection are influenced by the interplay between the virulence of the pathogen, the size of the inoculum, and the competence and nature of host defense mechanisms.

Virulence

Successful infection of ocular tissues requires microorganisms to adhere, evade, invade, replicate, and, in some instances, persist. Microbial virulence factors represent evolutionary adaptations by each microorganism that increase the odds of infection and organism survival.

Adherence

For ocular surface infections acquired exogenously, adherence of organisms to ocular surface epithelium is the first step.

Many bacteria express adhesins, which are microbial proteins that bind with high affinity to host cell surface molecules.

Candida albicans expresses surface proteins that mimic mammalian integrins (transmembrane proteins that mediate cell–cell and cell–extracellular matrix interactions).

Viruses typically express surface proteins or glycoproteins that attach to constitutive cell surface molecules such as heparan sulfate (herpes simplex virus) or sialic acid (adenovirus). Acanthamoeba express a mannose-binding protein that attaches to surface epithelial cells.

Evasion

Adherent bacteria evade interaction with unfavorable elements of their physical environment, such as immunologic cells or antibacterial molecules in the tears, by the expression of exopolysaccharides organized into a biofilm, a 3-dimensional structure that allows interbacterial communication and signaling and interferes with phagocytosis. For viruses, evasion of the immune response involves multiple strategies. For example, a herpes simplex virus (HSV)–encoded protein (eg, ICP47) successfully competes with antigenic viral peptides for transport into the endoplasmic reticulum, where peptides are loaded onto the major histocompatibility (MHC) complex. Thus, HSV-infected cells can be resistant to lysis by cytotoxic T cells.

McDougald D, Rice SA, Barraud N, Steinberg PD, Kjelleberg S. Should we stay or should we go: mechanisms and ecological consequences for biofilm dispersal. Nat Rev Microbiol. 2011;10(1):39–50.

Momburg F, Hengel H. Corking the bottleneck: the transporter associated with antigen processing as a target for immune subversion by viruses. Curr Top Microbiol Immunol. 2002;269:57–74.

Invasion

Few bacteria can overcome intact epithelium. Those that can, include

Neisseria gonorrhoeae

Neisseria meningitidis

Corynebacterium diphtheriae

Shigella spp

Haemophilus influenzae biotype III (formerly Haemophilus aegyptius)

Listeria monocytogenes

Others must rely on a break in the epithelial barrier function, when microbial proteases that induce cell lysis, degrade the extracellular matrix, and activate native corneal matrix–derived metalloproteinases (MMPs), triggering autodigestion, facilitate invasion. Bacterial exotoxins, such as those produced by streptococci, staphylococci, and Pseudomonas aeruginosa, can induce corneal cell necrosis. Acanthamoeba species and certain fungi secrete collagenases, whereas Pseudomonas elastase and alkaline protease destroy collagen and proteoglycan components of the cornea and degrade immunoglobulins, complement, interleukins, and other inflammatory cytokines. For viruses, adherence interactions facilitate invasion by the appropriation of host cell mechanisms. Interaction of adenovirus capsid proteins and host cell integrins, for example, triggers an intracellular signaling cascade that culminates in actin polymerization and endocytosis of the virus.

Replication and persistence

Most organisms are cleared from the site of infection following acute infection, but some persist in the host indefinitely. For example, following primary infection, HSV and varicella-zoster virus (VZV) establish latency in trigeminal ganglion cells. Chlamydia survives and causes local chronic disease by persistence within intracellular phagosomes.

Inoculum

Inoculum size, combined with the virulence factors of a particular species, determines the likelihood of establishing an infection and often its severity. With highly pathogenic organisms, a smaller number of organisms can cause infection and vice versa. The status of host defense mechanisms further determines the threshold of inoculum at which infection may occur.

Host Defense

Intrinsic anatomical mechanisms

Intrinsic anatomical mechanisms, including the following, may predispose the eye to infection:

Desiccation of the ocular surface epithelium may result from anatomical exposure, a reduced blink reflex, ocular surface disease, and keratoconjunctivitis sicca.

Microtrauma to the epithelium occurs with trichiasis, contact lens wear, and use of preservativecontaining topical medications.